AU7777100A - Bicyclic imidazo-3-yl-amine derivatives - Google Patents
Bicyclic imidazo-3-yl-amine derivatives Download PDFInfo
- Publication number
- AU7777100A AU7777100A AU77771/00A AU7777100A AU7777100A AU 7777100 A AU7777100 A AU 7777100A AU 77771/00 A AU77771/00 A AU 77771/00A AU 7777100 A AU7777100 A AU 7777100A AU 7777100 A AU7777100 A AU 7777100A
- Authority
- AU
- Australia
- Prior art keywords
- imidazo
- amine
- pyridin
- butyl
- tert
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 125000002619 bicyclic group Chemical group 0.000 title claims description 17
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 68
- -1 1,1,3,3-tetramethylbutyl Chemical group 0.000 claims description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 150000002527 isonitriles Chemical class 0.000 claims description 14
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 12
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- GXOBXLHECBUGTD-UHFFFAOYSA-N n-butyl-2-(2-methylphenyl)imidazo[1,2-a]pyrimidin-3-amine Chemical compound N1=C2N=CC=CN2C(NCCCC)=C1C1=CC=CC=C1C GXOBXLHECBUGTD-UHFFFAOYSA-N 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- GFLHPLKXODRDKS-UHFFFAOYSA-N 2-(1h-pyrrol-2-yl)-n-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrimidin-3-amine Chemical compound N1=C2N=CC=CN2C(NC(C)(C)CC(C)(C)C)=C1C1=CC=CN1 GFLHPLKXODRDKS-UHFFFAOYSA-N 0.000 claims description 7
- VBLHGASEDWPBTM-UHFFFAOYSA-N 2-(3-bromothiophen-2-yl)-n-cyclohexylimidazo[1,2-a]pyridin-3-amine Chemical compound C1=CSC(C2=C(N3C=CC=CC3=N2)NC2CCCCC2)=C1Br VBLHGASEDWPBTM-UHFFFAOYSA-N 0.000 claims description 7
- DVAZTXNALBESBS-UHFFFAOYSA-N 2-(furan-2-yl)-n-(6-isocyanohexyl)imidazo[1,2-a]pyridin-3-amine Chemical compound N1=C2C=CC=CN2C(NCCCCCC[N+]#[C-])=C1C1=CC=CO1 DVAZTXNALBESBS-UHFFFAOYSA-N 0.000 claims description 7
- SMBRAFOTVLPARM-UHFFFAOYSA-N 3-[3-(tert-butylamino)imidazo[1,2-a]pyridin-2-yl]phenol Chemical compound N1=C2C=CC=CN2C(NC(C)(C)C)=C1C1=CC=CC(O)=C1 SMBRAFOTVLPARM-UHFFFAOYSA-N 0.000 claims description 7
- 150000002431 hydrogen Chemical group 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- UIIYLFFNBBRBGX-UHFFFAOYSA-N 2-pyridin-4-yl-n-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrazin-3-amine Chemical compound N1=C2C=NC=CN2C(NC(C)(C)CC(C)(C)C)=C1C1=CC=NC=C1 UIIYLFFNBBRBGX-UHFFFAOYSA-N 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- YDHQSLJHCXALKX-UHFFFAOYSA-N n-(diethoxyphosphorylmethyl)-2-phenylimidazo[1,2-a]pyridin-3-amine Chemical compound N1=C2C=CC=CN2C(NCP(=O)(OCC)OCC)=C1C1=CC=CC=C1 YDHQSLJHCXALKX-UHFFFAOYSA-N 0.000 claims description 6
- AXOJDRXNPHURRH-UHFFFAOYSA-N n-butyl-2-(2,3-dichlorophenyl)imidazo[1,2-a]pyrazin-3-amine Chemical compound N1=C2C=NC=CN2C(NCCCC)=C1C1=CC=CC(Cl)=C1Cl AXOJDRXNPHURRH-UHFFFAOYSA-N 0.000 claims description 6
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 6
- QIACGFKYKKFJLH-UHFFFAOYSA-N 2-(2-chloro-4-fluorophenyl)-n-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrimidin-3-amine Chemical compound N1=C2N=CC=CN2C(NC(C)(C)CC(C)(C)C)=C1C1=CC=C(F)C=C1Cl QIACGFKYKKFJLH-UHFFFAOYSA-N 0.000 claims description 5
- FBFJMRUHTKUKAN-UHFFFAOYSA-N 2-(3,4,5-trimethoxyphenyl)-n-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine Chemical compound COC1=C(OC)C(OC)=CC(C2=C(N3C=CC=CC3=N2)NC(C)(C)CC(C)(C)C)=C1 FBFJMRUHTKUKAN-UHFFFAOYSA-N 0.000 claims description 5
- HDLUJJCNTDBGQQ-UHFFFAOYSA-N 2-anthracen-9-yl-n-tert-butylimidazo[1,2-a]pyrazin-3-amine Chemical compound C1=CC=C2C(C3=C(N4C=CN=CC4=N3)NC(C)(C)C)=C(C=CC=C3)C3=CC2=C1 HDLUJJCNTDBGQQ-UHFFFAOYSA-N 0.000 claims description 5
- 150000001409 amidines Chemical class 0.000 claims description 5
- FXHHUSLVJMVCSM-UHFFFAOYSA-N n-(6-isocyanohexyl)-2-pyridin-2-ylimidazo[1,2-a]pyridin-3-amine Chemical compound N1=C2C=CC=CN2C(NCCCCCC[N+]#[C-])=C1C1=CC=CC=N1 FXHHUSLVJMVCSM-UHFFFAOYSA-N 0.000 claims description 5
- HFVIQGNMAGCUCK-UHFFFAOYSA-N n-cyclohexyl-n-[2-(4,5-dimethylfuran-2-yl)imidazo[1,2-a]pyrimidin-3-yl]acetamide Chemical compound C=1C(C)=C(C)OC=1C=1N=C2N=CC=CN2C=1N(C(=O)C)C1CCCCC1 HFVIQGNMAGCUCK-UHFFFAOYSA-N 0.000 claims description 5
- SZEUAPUHWFRARK-UHFFFAOYSA-N n-cyclohexyl-n-[2-(5-methylfuran-2-yl)imidazo[1,2-a]pyridin-3-yl]acetamide Chemical compound C=1C=C(C)OC=1C=1N=C2C=CC=CN2C=1N(C(=O)C)C1CCCCC1 SZEUAPUHWFRARK-UHFFFAOYSA-N 0.000 claims description 5
- SZWLZKCBRXYYRA-UHFFFAOYSA-N n-tert-butyl-2-naphthalen-1-ylimidazo[1,2-a]pyridin-3-amine Chemical compound C1=CC=C2C(C3=C(N4C=CC=CC4=N3)NC(C)(C)C)=CC=CC2=C1 SZWLZKCBRXYYRA-UHFFFAOYSA-N 0.000 claims description 5
- KWXQPJCBTYCUGX-UHFFFAOYSA-N n-tert-butyl-2-pyridin-3-ylimidazo[1,2-a]pyrimidin-3-amine Chemical compound N1=C2N=CC=CN2C(NC(C)(C)C)=C1C1=CC=CN=C1 KWXQPJCBTYCUGX-UHFFFAOYSA-N 0.000 claims description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- ONTGILWWXJESRJ-UHFFFAOYSA-N methyl 2-[[2-(furan-2-yl)imidazo[1,2-a]pyrazin-3-yl]amino]acetate Chemical compound N1=C2C=NC=CN2C(NCC(=O)OC)=C1C1=CC=CO1 ONTGILWWXJESRJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- LBUVDABAAFTBPI-UHFFFAOYSA-N n-tert-butyl-2-methylimidazo[1,2-a]pyridin-3-amine Chemical compound C1=CC=CN2C(NC(C)(C)C)=C(C)N=C21 LBUVDABAAFTBPI-UHFFFAOYSA-N 0.000 claims description 4
- ORDKAKDRMJQWGP-UHFFFAOYSA-N n-tert-butyl-2-thiophen-2-ylimidazo[1,2-a]pyridin-3-amine Chemical compound N1=C2C=CC=CN2C(NC(C)(C)C)=C1C1=CC=CS1 ORDKAKDRMJQWGP-UHFFFAOYSA-N 0.000 claims description 4
- KBXQSAAAVZYHTC-UHFFFAOYSA-N 2-methyl-n-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrazin-3-amine Chemical compound C1=NC=CN2C(NC(C)(C)CC(C)(C)C)=C(C)N=C21 KBXQSAAAVZYHTC-UHFFFAOYSA-N 0.000 claims description 3
- VBRCIDLFXIVZHW-UHFFFAOYSA-N methyl 2-[(2-cyclohexylimidazo[1,2-a]pyrimidin-3-yl)amino]acetate Chemical compound N1=C2N=CC=CN2C(NCC(=O)OC)=C1C1CCCCC1 VBRCIDLFXIVZHW-UHFFFAOYSA-N 0.000 claims description 3
- LJEAFEJKWFRIJU-UHFFFAOYSA-N methyl 2-[(2-methylimidazo[1,2-a]pyrazin-3-yl)amino]acetate Chemical compound C1=NC=CN2C(NCC(=O)OC)=C(C)N=C21 LJEAFEJKWFRIJU-UHFFFAOYSA-N 0.000 claims description 3
- CKFBCHGNXAGKQZ-UHFFFAOYSA-N n-(2,6-dimethylphenyl)-2-(2-methoxyphenyl)imidazo[1,2-a]pyrazin-3-amine Chemical compound COC1=CC=CC=C1C1=C(NC=2C(=CC=CC=2C)C)N2C=CN=CC2=N1 CKFBCHGNXAGKQZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- HKCUKYRHQVXRFQ-UHFFFAOYSA-N n-tert-butyl-2-(5-methylsulfanylthiophen-2-yl)imidazo[1,2-a]pyrimidin-3-amine Chemical compound S1C(SC)=CC=C1C1=C(NC(C)(C)C)N2C=CC=NC2=N1 HKCUKYRHQVXRFQ-UHFFFAOYSA-N 0.000 claims description 3
- 230000036407 pain Effects 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 2
- 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 2
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Natural products C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 2
- 150000001454 anthracenes Chemical class 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims description 2
- 239000012948 isocyanate Substances 0.000 claims description 2
- 150000002513 isocyanates Chemical class 0.000 claims description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 150000002987 phenanthrenes Chemical class 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 150000003233 pyrroles Chemical class 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 150000003577 thiophenes Chemical class 0.000 claims description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims 1
- 125000006309 butyl amino group Chemical group 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- MJUJXFBTEFXVKU-UHFFFAOYSA-N diethyl phosphonate Chemical compound CCOP(=O)OCC MJUJXFBTEFXVKU-UHFFFAOYSA-N 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 claims 1
- 239000000243 solution Substances 0.000 description 87
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 34
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 28
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 description 9
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 9
- FAGLEPBREOXSAC-UHFFFAOYSA-N tert-butyl isocyanide Chemical compound CC(C)(C)[N+]#[C-] FAGLEPBREOXSAC-UHFFFAOYSA-N 0.000 description 9
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 8
- 150000004702 methyl esters Chemical class 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- YVPXQMYCTGCWBE-UHFFFAOYSA-N 2-isocyano-2,4,4-trimethylpentane Chemical compound CC(C)(C)CC(C)(C)[N+]#[C-] YVPXQMYCTGCWBE-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- YALISRCPDJICPH-UHFFFAOYSA-N 2-cyclohexyl-n-(6-isocyanohexyl)imidazo[1,2-a]pyrazin-3-amine Chemical compound N1=C2C=NC=CN2C(NCCCCCC[N+]#[C-])=C1C1CCCCC1 YALISRCPDJICPH-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 5
- 239000012346 acetyl chloride Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- XYZMOVWWVXBHDP-UHFFFAOYSA-N cyclohexyl isocyanide Chemical compound [C-]#[N+]C1CCCCC1 XYZMOVWWVXBHDP-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- IYWRAEJAOBUUER-UHFFFAOYSA-N n,2-ditert-butylimidazo[1,2-a]pyridin-3-amine Chemical compound C1=CC=CN2C(NC(C)(C)C)=C(C(C)(C)C)N=C21 IYWRAEJAOBUUER-UHFFFAOYSA-N 0.000 description 4
- LIQUJNIYWJECJB-UHFFFAOYSA-N n-cyclohexyl-2-(furan-2-yl)imidazo[1,2-a]pyridin-3-amine Chemical compound C1CCCCC1NC1=C(C=2OC=CC=2)N=C2N1C=CC=C2 LIQUJNIYWJECJB-UHFFFAOYSA-N 0.000 description 4
- BTFQKIATRPGRBS-UHFFFAOYSA-N o-tolualdehyde Chemical compound CC1=CC=CC=C1C=O BTFQKIATRPGRBS-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- WJCPMQQLTJQIJK-UHFFFAOYSA-N 1,6-diisocyanohexane Chemical compound [C-]#[N+]CCCCCC[N+]#[C-] WJCPMQQLTJQIJK-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
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- 239000004793 Polystyrene Substances 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000347391 Umbrina cirrosa Species 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 229940124339 anthelmintic agent Drugs 0.000 description 1
- 239000000921 anthelmintic agent Substances 0.000 description 1
- YMNKUHIVVMFOFO-UHFFFAOYSA-N anthracene-9-carbaldehyde Chemical compound C1=CC=C2C(C=O)=C(C=CC=C3)C3=CC2=C1 YMNKUHIVVMFOFO-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 230000002930 anti-sclerotic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004799 bromophenyl group Chemical group 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- QSACPWSIIRFHHR-UHFFFAOYSA-N dimethylphenyl isocyanide Natural products CC1=CC=CC(C)=C1C#N QSACPWSIIRFHHR-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000005232 imidazopyridines Chemical class 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000006452 multicomponent reaction Methods 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
WO 01/27111 PCT/EPOO/09096 Patent Application of Grunenthal GmbH, D-52078 Aachen (our reference: G 2906) Bicyclic imidazo-3-yl-amine derivatives 5 The present invention relates to substituted bicyclic imidazo-3-yl-amines and medicaments comprising these compounds. 10 Interesting pharmacological properties are known for individual compounds from the class of imidazo-3-yl-amines. Thus, certain imidazo[1,2-a]pyridines are known as active compounds which lower blood pressure (GB-B-1,135,893), as anthelmintics and antimycotics (J. Med. Chem. 1972, 15, 15 982-985) and as antisclerotic active compounds for the treatment of inflammatory diseases (EP-A-0 068 378). EP-A 0 266 890 and J. Med. Chem. 1987, 30, 2031-2046 also describe an action of individual imidazopyridines against inflammatory diseases, in particular of the stomach. 20 Further pharmacological actions described for individual representatives from the class of imidazo-3-yl-amines are antibacterial properties (Chem. Pharm. Bull. 1992, 40, 1170), antiviral properties (J. Med. Chem. 1998, 41, 5108 5112) and the action as a benzodiazepine receptor 25 antagonist (J. Heterocyclic Chem. 1998, 35, 1205-1217). In view of these interesting actions, various representatives from the class of substituted imidazo-3-yl amines have been synthesized in the past. In particular, 30 attempts have been made to increase the number of substituted imidazo-3-yl-amines available by combinatory synthesis processes. Thus, C. Blackburn et al. describe a three-component solid phase synthesis for the preparation of imidazo-3-yl-amines in Tetrahedron Lett. 1998, 39, 5469- WO 01/27111 PCT/EPOO/09096 2 5472 and a three-component condensation for parallel synthesis of imidazo-3-yl-amines in Tetrahedron Lett. 1998, 39, 3635-3638. The synthesis published by K. Groebke et al. in Synlett 1998, 661-663 is similar to the latter 5 reaction. A multi-component reaction for combinatory synthesis of imidazo-3-yl-amines, with which individual imidazo-5-amines have also been prepared, is also described by H. Bienayme and K. Bouzid in Angew. Chem. 1998, 110 (16), 2349-2352. 10 However, the range of variation possible according to the prior art for the substituents on the amino nitrogen and in the 2-position of the imidazole ring was limited. 15 The present invention was therefore based on the object of providing further bicyclic imidazo-3-yl-amines, and medicaments comprising these compounds. The invention therefore provides bicyclic imidazo-3-yl 20 amines of the general formula I R3 R1--N\ R2 25 WO 01/27111 PCT/EPOO/09096 3 wherein 5 X and Y denote CH or N, with the proviso that X and Y do not simultaneously denote N,
R
1 denotes tert-butyl, (CH 2 )nCN, where n = 4, 5 or 6, optionally substituted phenyl, C 4 -CB-cycloalkyl, CH 2
CH
2 R (R = 10 4-morpholino), 1,1,3,3-tetramethylbutyl or CH 2 Ra, wherein Ra represents hydrogen, OH, Ci-C 8 -alkyl (branched or unbranched), optionally substituted phenyl, CO(OR') (where R' = unbranched C 1
-C
4 -alkyl or branched Ci-C-alkyl),
PO(OR')
2 (where R' = unbranched C1-C 4 -alkyl or branched C1 15 C 5 -alkyl) or Si(RxRyRz) (where Rx, RY and Rz in each case independently of one another are C 1
-C
4 -alkyl (branched or unbranched), C 4 -C-cycloalkyl or phenyl),
R
2 denotes hydrogen, CORb, wherein Rb represents C 1
-C
4 -alkyl 20 (branched or unbranched) or C 3
-C
8 -cycloalkyl, CH 2
CH
2 CO(ORc), wherein RC represents C 1
-C
4 -alkyl (branched or unbranched), adamantyl, optionally substituted phenyl, optionally substituted 1-naphthyl or 2-naphthyl or in each case optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, dd 25 thiazolyl or furoyl, CH 2 phenyl, CH 2
CH
2 R , wherein R represents optionally substituted phenyl, or CONHR, wherein Re represents C 1
-C
8 -alkyl (branched or unbranched), C 3
-C
8 cycloalkyl or optionally substituted phenyl, 30 R 3 denotes methyl, ethyl, tert-butyl, C 3 -C-cycloalkyl, phenyl, optionally monosubstituted in the 3-, 5- or 6 position or optionally polysubstituted in the 4-position and additionally in the 2- and/or 3- and/or 5- and/or 6- WO 01/27111 PCT/EPOO/09096 4 position, phenoxy, optionally substituted naphthyl, optionally substituted pyrrole, optionally substituted pyridyl, optionally substituted furan, optionally substituted thiophene, optionally substituted anthracene, 5 optionally substituted phenanthrene or optionally substituted quinoline, with the proviso that R 3 does not denote n-propyl, cyclohexyl, unsubstituted phenyl or phenyl monosubstituted 10 in the 3-position with a carboxylic acid amide group if R 1 denotes t-butyl, n-propyl, n-butyl, 1,1,3,3 tetramethylbutyl, cyclohexyl, CH 2
CH
2 R (R = 4-morpholino), monosubstituted phenyl, 2,6-dimethylphenyl or benzyl and at the same time R 2 denotes hydrogen or -CO(methyl), and that 15 R 2 does not denote hydrogen if at the same time R 1 denotes benzyl and R 3 denotes methyl, or at the same time R 1 denotes
CH
2 C(0) tert-butyl and R 3 denotes unsubstituted phenyl, in the form of the bases or of pharmaceutically acceptable salts. 20 Compounds which are preferred here according to the invention are those in which R 2 denotes hydrogen, Rl is selected from the group consisting of (CH 2 )nCN, where n = 4, 5 or 6, cyclohexyl, CH 2 CO(Omethyl), 2,6-dimethylphenyl, 25 1,1,3,3-tetramethylbutyl, tert-butyl or n-butyl and R 3 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 2-furanyl, 2-pyrroyl, methyl, tert-butyl, 3-hydroxyphenyl, 3,4-dimethoxyphenyl, 2,3-dichlorophenyl, 2,4 dichlorophenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 3 30 bromophenyl, 4-bromo-2-fluorophenyl, 5-bromo-2 fluorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, 3,4 dichlorophenyl, 3-fluorophenyl, 3-methylphenyl, 3 phenoxyphenyl, 3-(4-chlorophenoxy)phenyl, 2-chloro-4- WO 01/27111 PCT/EPOO/09096 5 fluorophenyl, 2-chloro-6-fluorophenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2-bromophenyl, 2-fluorophenyl or 2 (trifluoromethyl)-phenyl. 5 Compounds which are particularly preferred according to the invention are bicyclic imidazo-3-yl-amines selected from the group consisting of (6-isocyano-hexyl)-(2-pyridin-2-yl-imidazo[1,2-a]pyridin-3 10 yl)-amine, (2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-(6-isocyano hexyl)-amine, (2-cyclohexyl-imidazo[1,2-a]pyrazin-3-yl)-(6-isocyano hexyl)-amine, 15 (2,6-dimethyl-phenyl)-(2-furan-2-yl-imidazo[1,2-a]pyridin 3-yl)-amine, (2-furan-2-yl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid methyl ester, (2-cyclohexyl-imidazo[1,2-a]pyrimidin-3-ylamino)-acetic 20 acid methyl ester, (2-methyl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid methyl ester, (2-pyridin-4-yl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3 tetramethyl-butyl)-amine, 25 (2-methyl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3-tetramethyl butyl)-amine, 3-(3-tert-butylamino-imidazo[1,2-a]pyridin-2-yl)-phenol, butyl-[2-(2,3-dichloro-phenyl)-imidazo[1,2-a]pyrazin-3-yl] amine, 30 [(2-phenyl-imidazo[1,2-a]pyridin-3-ylamino)-methyl] phosphonic acid diethyl ester, tert-butyl-(2-tert-butyl-imidazo[1,2-a]pyridin-3-yl)-amine, butyl-(2-o-tolyl-imidazo[1,2-a]pyrimidin-3-yl)-amine, WO 01/27111 PCT/EPOO/09096 6 (2,6-dimethyl-phenyl)-[2-(2-methoxy-phenyl)-imidazo[1,2 a]pyrazin-3-yl]-amine, butyl-(2-o-tolyl-imidazo[1,2-a]pyrimidin-3-yl)-amine, tert-butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyrimidin-3-yl) 5 amine, tert-butyl-(2-methyl-imidazo[1,2-ajpyridin-3-yl)-amine, [2-(1H-pyrrol-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-(1,1,3,3 tetramethyl-butyl)-amine, cyclohexyl-(2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine, 10 tert-butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyridin-3-yl) amine, tert-butyl-(2-pyridin-2-yl-imidazo[1,2-a]pyridin-3-yl) amine, tert-butyl-(2-thiophen-2-yl-imidazo[1,2-a]pyridin-3-yl) 15 amine, cyclohexyl-(2-methyl-imidazo[1,2-alpyridin-3-yl)-amine, N-cyclohexyl-N-[2-(5-methyl-furan-2-yl)-imidazo[1,2 a]pyridin-3-yl]-acetamide, tert-butyl-[2-(5-methylsulfanyl-thiophen-2-yl)-imidazo[1,2 20 a]pyrimidin-3-yl]-amine, [2-(3-bromo-thiophen-2-yl)-imidazo[1,2-a]pyridin-3-yl] cyclohexyl-amine, acetic acid 2-methoxy-4-[3-(1,1,3,3-tetramethyl butylamino)-imidazo[1,2-a]pyrimidin-2-yl]-phenyl ester, 25 [2-(2-chloro-4-fluoro-phenyl)-imidazo[1,2-a]pyrimidin-3 yll-(1,1,3,3-tetramethylbutyl)-amine, (2-anthracen-9-yl-imidazo[1,2-a]pyrazin-3-yl)-tert-butyl amine, tert-butyl-(2-naphthalen-1-yl-imidazo[1,2-a]pyridin-3-yl) 30 amine, N-cyclohexyl-N-[2-(4,5-dimethyl-furan-2-yl)-imidazo[1,2 a]pyrimidin-3-yl]-acetamide or WO 01/27111 PCT/EPOO/09096 7 (1,1,3,3-tetramethylbutyl)-[2-(3,4,5-trimethoxy-phenyl) imidazo[1,2-a]pyridin-3-yll-amine. If the bicyclic imidazo-3-yl-amines according to the 5 invention contain optically active carbon atoms, the present invention also provides the enantiomers of these compounds and mixtures thereof. The invention furthermore provides medicaments comprising 10 as the active compound at least one bicyclic imidazo-3-yl amine of the general formula I, in which R 1 to R 3 , X and Y have the abovementioned meaning, in the form of the base or of pharmaceutically acceptable salts, preferably of hydrobromic acid, sulfuric acid, methanesulfonic acid, 15 formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid, or in particular of hydrochloric acid. 20 Surprisingly, it has been found here that the compounds according to the invention not only are potential active compounds for the indications mentioned in the prior art, but also show an analgesic action. 25 The medicaments according to the invention particularly preferably comprise as the active compound at least one bicyclic imidazo-3-yl-amine selected from the group consisting of (6-isocyano-hexyl)-(2-pyridin-2-yl-imidazo[1,2-a]pyridin-3 30 yl)-amine, (2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-(6-isocyano hexyl)-amine, WO 01/27111 PCT/EPOO/09096 8 (2-cyclohexyl-imidazo[1,2-a]pyrazin-3-yl)-(6-isocyano hexyl)-amine, (2,6-dimethyl-phenyl)-(2-furan-2-yl-imidazo[1,2-a]pyridin 3-yl)-amine, 5 (2-furan-2-yl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid methyl ester, (2-cyclohexyl-imidazo[1,2-a]pyrimidin-3-ylamino)-acetic acid methyl ester, (2-methyl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid 10 methyl ester, (2-pyridin-4-yl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3 tetramethyl-butyl)-amine, (2-methyl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3-tetramethyl butyl)-amine, 15 3-(3-tert-butylamino-imidazo[1,2-a]pyridin-2-yl)-phenol, butyl-[2-(2,3-dichloro-phenyl)-imidazo[1,2-a]pyrazin-3-yl] amine, [(2-phenyl-imidazo[1,2-a]pyridin-3-ylamino)-methyl] phosphonic acid diethyl ester, 20 tert-butyl-(2-tert-butyl-imidazo[1,2-a]pyridin-3-yl)-amine, butyl-(2-o-tolyl-imidazo[1,2-a]pyrimidin-3-yl)-amine, (2,6-dimethyl-phenyl)-[2-(2-methoxy-phenyl)-imidazo[1,2 alpyrazin-3-yl]-amine, butyl-(2-o-tolyl-imidazo[1,2-a]pyrimidin-3-yl)-amine, 25 tert-butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyrimidin-3-yl) amine, tert-butyl-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-amine, [2-(1H-pyrrol-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-(1,1,3,3 tetramethyl-butyl)-amine, 30 cyclohexyl-(2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine, tert-butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyridin-3-yl) amine, WO 01/27111 PCT/EPOO/09096 9 tert-butyl-(2-pyridin-2-yl-imidazo[1,2-a]pyridin-3-yl) amine, tert-butyl-(2-thiophen-2-yl-imidazo[1,2-a]pyridin-3-yl) amine, 5 cyclohexyl-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-amine, N-cyclohexyl-N-[2-(5-methyl-furan-2-yl)-imidazo[1,2 alpyridin-3-yl]-acetamide, tert-butyl-[2-(5-methylsulfanyl-thiophen-2-yl)-imidazo[1,2 alpyrimidin-3-yl]-amine, 10 [2-(3-bromo-thiophen-2-yl)-imidazo[1,2-a]pyridin-3-yl] cyclohexyl-amine, acetic acid 2-methoxy-4-[3-(1,1,3,3-tetramethyl butylamino)-imidazo[1,2-a]pyrimidin-2-yl]-phenyl ester, [2-(2-chloro-4-fluoro-phenyl)-imidazo[1,2-a]pyrimidin-3 15 yl]-(1,1,3,3-tetramethylbutyl)-amine, (2-anthracen-9-yl-imidazo[1,2-alpyrazin-3-yl)-tert-butyl amine, tert-butyl-(2-naphthalen-1-yl-imidazo[1,2-a]pyridin-3-yl) amine, 20 N-cyclohexyl-N-[2-(4,5-dimethyl-furan-2-yl)-imidazo[1,2 a]pyrimidin-3-yl]-acetamide or (1,1,3,3-tetramethylbutyl)-[2-(3,4,5-trimethoxy-phenyl) imidazo[1,2-a]pyridin-3-yl]-amine, or the pharmaceutically acceptable salts of these compounds. 25 The use of the bicyclic imidazo-3-yl-amines according to the invention together with one or more auxiliary substances for the preparation of a medicament for combating pain is particularly preferred here. 30 For the preparation of appropriate medicaments, in addition to at least one active compound according to the invention, one or more auxiliary substances, preferably carrier WO 01/27111 PCT/EPOO/09096 10 materials, fillers, solvents, diluents, dyestuffs and/or binders, are employed. The choice of auxiliary substances and the amounts thereof to be employed depend on whether the medicament is to be administered orally, intravenously, 5 intraperitoneally, intradermally, intramuscularly, intranasally, buccally or locally. Formulations in the form of tablets, coated tablets, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, easily reconstitutable dry 10 formulations and sprays are suitable for parenteral, topical and inhalatory administration. Active compounds according to the invention in a depot, in dissolved form or in a patch, optionally with the addition of agents which promote penetration through the skin, are suitable 15 formulations for percutaneous administration. Formulation forms which can be used orally or percutaneously can release the active compounds according to the invention in a retarded manner. 20 The amount of active compound to be administered to the patient varies according to the weight of the patient, and to the mode of administration, the indication and the severity of the disease. 25 The compounds according to the invention are synthesized by a procedure in which amidines with the general formula II, in particular 2-aminopyridine, 2-aminopyrazine and 2 aminopyrimidine derivatives, which are commercially available from companies such as, for example, Acros, 30 Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma or TCI-Jp, are reacted with the most diverse ketones or, preferably, aldehydes III and isonitriles IV in the presence of 20% perchloric acid in accordance with a three- WO 01/27111 PCT/EPOO/09096 11 component reaction. R 1 to R 3 , X and Y here have the meaning given above for compounds of the formula I. H H
..
N X ' R3- R1-N=c H IIIy For a problem-free course of the reaction, it is essential 5 here that the starting compounds are added successively in the sequence amidine II, aldehyde III and isonitrile IV. The reactions are preferably carried out in methylene chloride at a temperature of preferably 00C to 400C, in particular at a temperature of 10'C to 20*C. 10 To prepare the compounds according to the invention in which R 2 does not denote hydrogen, the compounds Ia formed in the reaction described above, which have preferably first been dissolved in THF, are reacted, depending on the 15 desired end product, with a compound R 2Hal, wherein Hal represents bromine, iodine or, in particular, chlorine, for example an optionally substituted alkyl, aryl or acid chloride, or an optionally substituted isocyanate ReNCO in the presence of a morpholine resin (e.g. polystyrene 20 morpholine from Argonaut) in methylene chloride in the course of 2 to 24 hours at temperatures between 100C and 40*C in accordance with the following equation: WO 01/27111 PCT/EPOO/09096 12 N R3- R1'N la 1. ) R 2 Hal or ReNCO polymer-bonded morpholine; MC, T = 10-40*C, 2-24h 2. ) polymer-bonded Tris (2 aminoethyl) amine R3 R1'N R2 The excess reagents are then removed from the reaction mixtures by filtration over a layer with polymer-bonded 5 tris(2-aminoethyl)amine (manufacturer: Novabiochem) or 3 (3-mercaptophenyl)propanamidomethylpolystyrene and the filtrate is preferably concentrated in a vacuum centrifuge. The entire process can also easily be carried out in an automated synthesis unit. 10 WO 01/27111 PCT/EPOO/09096 13 The compounds of the formula I can be converted into their salts in a manner known per se with physiologically tolerated acids, preferably hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, 5 oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid, and in particular hydrochloric acid. The salt formation is preferably carried out in a solvent, preferably diethyl ether, diisopropyl ether, acetic acid 10 alkyl esters, acetone or 2-butanone, or a mixture of these solvents. Alternatively, trimethylsilane in aqueous solution is also suitable for preparation of the hydrochlorides. 15 Examples: The following examples are intended to illustrate the invention without limiting it thereto. 20 General instructions 1 (automatic synthesis) The synthesis of the compounds was carried out in an automatic unit from Zymark in accordance with the following general synthesis instructions: 25 A round-bottomed tube of glass (diameter 16 mm, length 125 mm) with a thread was provided manually with a stirrer and closed with a screw-cap with a septum on the capper station. The tube was placed by robot 1 in the reactor 30 block temperature-controlled at 15 0 C. Robot 2 pipetted in the following reagents in succession: WO 01/27111 PCT/EPOO/09096 14 1.) 1 ml of a 0.1 M amidine solution + 20% HC10 4 in methylene chloride 2.) 0.5 ml of a 0.3 M aldehyde solution in methylene chloride 5 3.) 0.575 ml of a 0.2 M isonitrile solution in methylene chloride The reaction mixture was stirred at 15 0 C in one of the stirring blocks for 660 min. Thereafter, the reaction 10 solution was filtered at the filtration station. The tube was rinsed here twice with in each case 1 ml methylene chloride and 200 pl water. The rack with the tubes was then placed manually on the 15 working-up unit. On this, 3 ml of a 10% NaCl solution and 1.5 ml methylene chloride were added to the reaction mixture on a vortexer. The components were mixed thoroughly in the spin reactor for ten minutes and a clear phase boundary was formed by slowly decreasing the 20 rotational movement. This phase boundary was detected optically and the organic phase was pipetted off. In the next step, 1.5 ml methylene chloride were again added to the reaction mixture. The solution was shaken and centrifuged and the organic phase was pipetted off. The 25 combined organic phases were dried over 2.4 g MgSO 4 (granulated). The solvent was removed in a vacuum centrifuge. General instructions 2 (manual synthesis) 30 (Equivalents denote molar equivalents, based on the isonitrile employed): WO 01/27111 PCT/EPOO/09096 15 1.15 equivalents of the heterocyclic amine were first suspended or dissolved in methylene chloride (2 ml per mmol of isonitrile employed) in a suitable reaction vessel. 1.5 equivalents of aldehyde, one equivalent of isonitrile 5 and finally aqueous perchloric acid solution (20 m%; 0.098 ml per mmol of isonitrile employed) were added to this in succession and the mixture was stirred at room temperature for twenty hours. 10 For working up, saturated sodium chloride solution (approx. 5 ml per mmol of isonitrile employed) and methylene chloride (approx. 4 ml per mmol of isonitrile employed) were added, the phases were separated and the organic phase was extracted twice more with methylene chloride (in each 15 case approx. 2 ml per mmol of isonitrile employed). The combined organic phases were washed in succession with buffer solution (pH 10; approx. 2 ml per mmol of isonitrile employed) and sat. sodium chloride solution (approx. 2 ml per mmol of isonitrile employed), dried over sodium sulfate 20 and filtered, the filtrate was concentrated on a rotary evaporator in vacuo and the residue was freed from solvent residues under an oil pump vacuum. The chemicals and solvents employed were obtained 25 commercially. Each substance was analysed by ESI-MS and/or
NMR.
WO 01/27111 PCT/EPOO/09096 16 General instructions 3 (reaction with acetyl chloride) The product obtained in accordance with general instructions 1 was dissolved in methylene chloride, 4 molar 5 equivalents of acetyl chloride were added and the mixture was stirred at 180C for four hours. The excess acetyl chloride and the solvent were removed in vacuo at 40-60*C. Each substance was analysed by ESI-MS. 10 Example 1 (6-Isocyano-hexyl)-(2-pyridin-2-yl-imidazo[1,2-a]pyridin-3 yl)-amine (1) Compound 1 was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyridine solution (0.1 M, 15 MC), 0.575 ml 1,6-diisocyanohexane solution (0.2 M, MC), 0.500 ml pyridine-2-carbaldehyde solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%). Calculated mass 321.43; found mass M-H = 320.4 (ESI-MS) 20 Example 2 (2-Furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-(6-isocyano hexyl)-amine (2) Compound 2 was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyridine solution (0.1 M, 25 MC), 0.575 ml 1,6-diisocyanohexane solution (0.2 M, MC), 0.500 ml furfural solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%). Calculated mass 310.40; found mass M-H = 309.4 (ESI-MS) 30 Example 3 (2-Cyclohexyl-imidazo[1,2-a]pyrazin- 3 -yl)-(6-isocyano hexyl)-amine (3) WO 01/27111 PCT/EPOO/09096 17 Compound 3 was prepared in accordance with general instructions 1 from 1.0 ml aminopyrazine solution (0.1 M, MC), 0.575 ml 1,6-diisocyanohexane solution (0.2 M, MC), 0.500 ml cyclohexanecarbaldehyde solution (0.3 M, MC) and 5 10 ptl perchloric acid (w = 20%). Calculated mass 327.48; found mass M-H = 326.5 (ESI-MS) Example 4 (2,6-Dimethyl-phenyl)-2-furan-2-yl-imidazo[1,2-a]pyridin-3 10 yl)-amine (4) Compound 4 was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyridine solution (0.1 M, MC), 0.575 ml 2,6-dimethylphenylisonitrile solution (0.2 M, MC), 0.500 ml furfural solution (0.3 M, MC) and 10 pil 15 perchloric acid (w = 20%). Calculated mass 303.37; found mass = 304.4 (ESI-MS) Example 5 (2-Furan-2-yl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid 20 methyl ester (5) Compound 5 was prepared in accordance with general instructions 1 from 1.0 ml aminopyrazine solution (0.1 M, MC), 0.575 ml methyl isocyanoacetate solution (0.2 M, MC), 0.500 ml furfural solution (0.3 M, MC) and 10 pil perchloric 25 acid (w = 20%). Calculated mass 272.27; found mass = 273.4 (ESI-MS) Example 6 (2-Cyclohexyl-imidazo[1,2-a]pyrimidin-3-ylamino)-acetic 30 acid methyl ester (6) Compound 6 was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyrimidine solution WO 01/27111 PCT/EPOO/09096 18 (0.1 M, MC), 0.575 ml methyl isocyanoacetate solution (0.2 M, MC); 0.500 ml cyclohexylcarbaldehyde solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%). Calculated mass 288.35; found mass = 289.4 (ESI-MS) 5 Example 7 (2-Methyl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid methyl ester Compound 7 was prepared in accordance with general 10 instructions 1 from 1.0 ml aminopyrazine solution (0.1 M, MC), 0.575 ml methyl isocyanoacetate solution (0.2 M, MC), 0.500 ml acetaldehyde solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%). Calculated mass 220.23; found mass = 221.3 (ESI-MS 15 Example 8 (2-Pyridin-4-yl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3 tetramethyl-butyl)-amine (8) Compound 8 was prepared in accordance with general 20 instructions 1 from 1.0 ml aminopyrazine solution (0.1 M, MC), 0.575 ml 1,1,3,3-tetramethylbutyl isocyanide (0.2 M, MC), 0.500 ml pyridine-4-carbaldehyde solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%). Calculated mass 323.44; found mass = 324.4 (ESI-MS) 25 Example 9 (2-Methyl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3-tetramethyl butyl)-amine Compound 9 was prepared in accordance with general 30 instructions 1 from 1.0 ml aminopyrazine solution (0.1 M, MC), 0.575 ml 1,1,3,3-tetramethylbutyl isocyanide (0.2 M, WO 01/27111 PCT/EPOO/09096 19 MC), 0.500 ml acetaldehyde solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%). Calculated mass 260.39; found mass = 261.4 (ESI-MS) 5 Example 10 (3-(3-tert-Butylamino-imidazo[1,2-a]pyridin-2-yl)-phenol (10) Compound 10 was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyridine solution (0.1 M, 10 MC), 0.575 ml tert-butylisonitrile solution (0.2 M, MC), 0.500 ml 3-hydroxybenzaldehyde solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%). Calculated mass 281.36; found mass = 282.3 (ESI-MS) 15 Example 11 Butyl-[2-(2,3-dichloro-phenyl)-imidazo[1,2-a]pyrazin-3-yl] amine (11) Compound 11 was prepared in accordance with general instructions 1 from 1.0 ml aminopyrazine solution (0.1 M, 20 MC), 0.575 ml n-butylisonitrile solution (0.2 M, MC), 0.500 ml 2,3-dichlorobenzaldehyde solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%). Calculated mass 335.24; found mass = 335.4 (ESI-MS) 25 Example 12 [(2-Phenyl-imidazo[1,2-a]pyridin-3-ylamino)-methyl] phosphonic acid diethyl ester (12) Compound 12 was prepared in accordance with general instructions 2 from 2-aminopyridine, diethyl isocyanomethyl 30 phosphate, benzaldehyde and perchloric acid (w = 20%). The structure was confirmed by NMR spectroscopy.
WO 01/27111 PCT/EPOO/09096 20 Example 13 tert-Butyl-(2-tert-butyl-imidazo[1,2-a]pyridin-3-yl)-amine (13) Compound 13 was prepared in accordance with general 5 instructions 2 from 2-aminopyridine, tert-butylisonitrile, pivaldehyde and perchloric acid. The structure was confirmed by NMR spectroscopy. Example 14 10 Butyl-(2-o-tolyl-imidazo[1,2-alpyrimidin-3-yl)-amine (14) Compound 14 was prepared in accordance with the general instructions from 1.0 ml 2-aminopyrimidine solution (0.1 M, MC), 0.575 ml n-butylisonitrile solution (0.2 M, MC), 0.500 ml 2-methylbenzaldehyde solution (0.3 M, MC) and 15 10 pil perchloric acid (w = 20%). Calculated mass 280.38; found mass = 281.3 (ESI-MS) Example 15 (2,6-Dimethyl-phenyl)-[2-(2-methoxy-phenyl)-imidazo[1,2 20 alpyrazin-3-yl]-amine (15) Compound 15 was prepared in accordance with general instructions 1 from 1.0 ml aminopyrazine solution (0.1 M, MC), 0.575 ml 2,6-dimethylphenyl isocyanide solution (0.2 M, MC), 0.500 ml 2-methoxybenzaldehyde solution (0.3 M, MC) 25 and 10 pil perchloric acid (w = 20%). Calculated mass 344.42; found mass = 345.4 (ESI-MS) Example 16 Butyl-(2-o-tolyl-imidazo[1,2-a]pyrimidin-3-yl)-amine (16) 30 Compound 16 was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyrimidine solution (0.1 M, MC), 0.575 ml n-butylisonitrile solution (0.2 M, WO 01/27111 PCT/EPOO/09096 21 MC), 0.500 ml 2-methylbenzaldehyde solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%). Calculated mass 280.38; found mass = 281.3 (ESI-MS) 5 Example 17 tert-Butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyrimidin-3-yl) amine (17) Compound 17 was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyrimidine solution 10 (0.1 M, MC), 0.575 ml tert-butylisonitrile solution (0.2 M, MC), 0.500 ml pyridine-3-carbaldehyde solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%). Calculated mass 267.34; found mass = 268.3 (ESI-MS) 15 Example 18 tert-Butyl-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-amine (18) Compound 18 was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyridine solution (0.1 M, MC), 0.575 ml tert-butylisonitrile solution (0.2 M, MC), 20 0.500 ml acetaldehyde solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%). Calculated mass 203.29; found mass = 204.3 (ESI-MS) Example 19 25 [2-(lH-Pyrrol-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-(1,1,3,3 tetramethyl-butyl)-amine (19) Compound 19 was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyrimidine solution (0.1 M, MC), 0.575 ml 1,1,3,3-tetramethylbutyl isocyanide 30 solution (0.2 M, MC), 0.500 ml pyrrole-2-carbaldehyde solution (0.3 M, MC) and 10 pil perchloric acid (w = 20%). Calculated mass 311.43; found mass = 312.4 (ESI-MS) WO 01/27111 PCT/EPOO/09096 22 Example 20 Cyclohexyl-(2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine (20) 5 Compound 20 was prepared in accordance with general instructions 2 from 2-aminopyridine, cyclohexylisonitrile, furfural and perchloric acid. The structure was confirmed by NMR spectroscopy. 10 Example 21 tert-Butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyridin-3-yl) amine (21) Compound 21 was prepared in accordance with general instructions 2 from 2-aminopyridine, tert-butylisonitrile, 15 nicotinaldehyde and perchloric acid. The structure was confirmed by NMR spectroscopy. Example 22 tert-Butyl-(2-pyridin-2-yl-imidazo[1,2-a]pyridin-3-yl) 20 amine (22) Compound 22 was prepared in accordance with general instructions 2 from 2-aminopyridine, tert-butylisonitrile, 2-pyridylcarbaldehyde and perchloric acid. The structure was confirmed by NMR spectroscopy. 25 Example 23 tert-Butyl-(2-thiophen-2-yl-imidazo[1,2-a]pyridin-3-yl) amine (23) Compound 23 was prepared in accordance with general 30 instructions 2 from 2-aminopyridine, tert-butylisonitrile, thiophene-2-carbaldehyde and perchloric acid. The structure was confirmed by NMR spectroscopy.
WO 01/27111 PCT/EPOO/09096 23 Example 24 Cyclohexyl-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-amine (24) Compound 24 was prepared in accordance with general 5 instructions 2 from 2-aminopyridine, cyclohexylisonitrile, acetaldehyde and perchloric acid. The structure was confirmed by NMR spectroscopy. Example 25 10 N-Cyclohexyl-N-[2-(5-methyl-furan-2-yl)-imidazo[1,2 a]pyridin-3-yl]acetamide (25) Compound 25 was prepared by reaction of the product obtained in accordance with general instructions 1 from 1.0 ml 2-aminopyridine solution (0.1 M, MC), 0.575 ml 15 cyclohexyl isocyanide solution (0.2 M, MC), 0.500 ml 5 methylfurfural solution (0.3 M, MC) and 10 ptl perchloric acid (w = 20%) with acetyl chloride in accordance with general instructions 3. Calculated mass 337.4; found mass 338.5; M-acetyl 296.5 20 (ESI-MS) Example 26 tert-Butyl-[2-(5-methylsulfanyl-thiophen-2-yl)-imidazo[1,2 a]pyrimidin-3-yl]-amine (26) 25 Compound 26 was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyrimidine solution (0.1 M, MC), 0.575 ml tert-butylisonitrile isocyanide solution (0.2 M, MC), 0.500 ml 5-methylsulfanyl-thiophene 2-carbaldehyde solution (0.3 M, MC) and 10 pl perchloric 30 acid (w = 20%). Calculated mass 318.5; found mass 319.2
(ESI-MS)
WO 01/27111 PCT/EPOO/09096 24 Example 27 [2-(3-Bromo-thiophen-2-yl)-imidazo[1,2-a]pyridin-3-yl] cyclohexyl-amine (27) Compound 27 was prepared in accordance with general 5 instructions 1 from 1.0 ml 2-aminopyridine solution (0.1 M, MC), 0.575 ml cyclohexyl isocyanide solution (0.2 M, MC), 0.500 ml 3-bromothiophene-2-carbaldehyde solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%). Calculated mass 376.3; found mass 376.4/378.3 (ESI-MS) 10 Example 28 Acetic acid 2-methoxy-4-[3-(1,1,3,3-tetramethyl butylamino)-imidazo[1,2-a]pyrimidin-2-yll-phenyl ester (28) Compound 28 was prepared in accordance with general 15 instructions 1 from 1.0 ml 2-aminopyrimidine solution (0.1 M, MC), 0.575 ml 1,1,3,3-tetramethylbutyl isocyanide solution (0.2 M, MC), 0.500 ml acetic acid 4-formyl-2 methoxy-phenyl ester solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%). Calculated mass 410.5; found 20 mass 411.3 (ESI-MS) Example 29 [2-(2-Chloro-4-fluoro-phenyl)-imidazo[1,2-a]pyrimidin-3 yl]-(1,1,3,3-tetramethylbutyl)-amine (29) 25 Compound 29 was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyrimidine solution (0.1 M, MC), 0.575 ml 1,1,3,3-tetramethylbutyl isocyanide solution (0.2 M, MC), 0.500 ml 2-chloro-4 fluorobenzaldehyde solution (0.3 M, MC) and 10 pl 30 perchloric acid (w = 20%). Calculated mass 374.9; found mass 375.3 (ESI-MS) WO 01/27111 PCT/EPOO/09096 25 Example 30 (2-Anthracen-9-yl-imidazo[1,2-a]pyrazin-3-yl)-tert-butyl amine (30) Compound 30 was prepared in accordance with general 5 instructions 1 from 1.0 ml 2-aminopyrazine solution (0.1 M, MC), 0.575 ml tert-butyl isocyanide solution (0.2 M, MC), 0.500 ml anthracene-9-carbaldehyde solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%). Calculated mass 366.5; found mass 367.3 (ESI-MS) 10 Example 31 tert-Butyl-(2-naphthalen-1-yl-imidazo[1,2-a]pyridin-3-yl) amine (31) Compound 31 was prepared in accordance with general 15 instructions 1 from 1.0 ml 2-aminopyridine solution (0.1 M, MC), 0.575 ml tert-butyl isocyanide solution (0.2 M, MC), 0.500 ml naphthalene-l-carbaldehyde solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%). Calculated mass 315.4; found mass 316.3 (ESI-MS) 20 Example 32 N-Cyclohexyl-N-[2-(4,5-dimethyl-furan-2-yl)-imidazo[1,2 a]pyrimidin-3-yl]-acetamide (32) Compound 32 was prepared by reaction of the product 25 obtained in accordance with general instructions 1 from 1.0 ml 2-aminopyrimidine solution (0.1 M, MC), 0.575 ml cyclohexyl isocyanide solution (0.2 M, MC), 0.500 ml 4,5 dimethylfurfural solution (0.3 M, MC) and 10 pl perchloric acid (w = 20%) with acetyl chloride in accordance with 30 general instructions 3. Calculated mass 352.4; found mass 353.4 (ESI-MS) WO 01/27111 PCT/EPOO/09096 26 Example 33 (1,1,3,3-Tetramethylbutyl)-[2-(3,4,5-trimethoxy-phenyl) imidazo[1,2-a]pyridin-3-yl]-amine (33) Compound 33 was prepared in accordance with general 5 instructions 1 from 1.0 ml 2-aminopyridine solution (0.1 M, MC), 0.575 ml 1,1,3,3-tetramethylbutyl isocyanide solution (0.2 M, MC), 0.500 ml 3,4,5-trimethoxybenzaldehyde solution (0.3 M, MC) and 10 il perchloric acid (w = 20%). Calculated mass 411.5; found mass 412.3 (ESI-MS) 10 Analgesia test in the writhing test in mice The analgesic activity was investigated in the phenylquinone-induced writhing in mice (modified according 15 to I.C. Hendershot, J. Forsaith, J. Pharmacol. Exp. Ther. 125, 237-240 (1959)). Male NMRI mice weighing 25-30 g were used for this. Groups of 10 animals per substance dose received 0.3 ml/mouse of a 0.02% aqueous solution of phenylquinone (phenylbenzoquinone, Sigma, Deisenhofen; 20 preparation of the solution with the addition of 5% ethanol and storage in a water-bath at 45 0 C) administered intraperitoneally ten minutes after intravenous or subcutaneous administration of the test substances. The animals were placed individually in observation cages. The 25 number of pain-induced extension movements (so-called writhing reactions = straightening of the body with stretching out of the hind extremities) 5 - 20 minutes after administration of the phenylquinone was counted by means of a push-button counter. Animals which receive only 30 physiological saline solution were also run as a control. The substances were tested in the standard dosage of 10 mg/kg intravenously or 21.5 mg/kg subcutaneously. The percentage inhibition (% inhibition) of the writhing WO 01/27111 PCT/EPOO/09096 27 reaction by a substance was calculated in accordance with the following equation: 5 Writhing reactions % inhibition = 100 - of the treated animals * 100 Writhing reactions of the control animals 10 The compounds according to the invention investigated showed an analgesic action. The results are summarized in the following table. 15 Table: Analgesia test in the writhing test in mice % inhibition of the % inhibition of the Example writhing reaction writhing reaction at 21.5 mg/kg at 10 mg/kg subcutaneously intravenously 12 90 13 86 at 2.15 mg/kg 20 43 21 80 22 53 23 62 24 56
Claims (5)
1. Bicyclic imidazo-3-yl-amines of the general formula I R3 R1--N\ R2 5 wherein X and Y denote CH or N, with the proviso that X and Y do not simultaneously denote N, 10 R 1 denotes tert-butyl, (CH 2 )nCN, where n = 4, 5 or 6, optionally substituted phenyl, C 4 -CB-cycloalkyl, CH 2 CH 2 R (R = 4-morpholino), 1,1,3,3-tetramethylbutyl or CH 2 Ra, wherein Ra represents hydrogen, OH, CI-C 8 -alkyl 15 (branched or unbranched), optionally substituted phenyl, CO(OR') (where R' = unbranched C 1 -C 4 -alkyl or branched C 1 -C 5 -alkyl), PO(OR') 2 (where R' = unbranched C 1 -C 4 -alkyl or branched C 1 -C-alkyl) or Si(RxRYRz) (where Rx, Ry and Rz in each case independently of one another 20 are C 1 -C 4 -alkyl (branched or unbranched), C4-C8 cycloalkyl or phenyl), R2 denotes hydrogen, COR , wherein R represents CI-C 4 alkyl (branched or unbranched) or C 3 -CB-cycloalkyl, 25 CH 2 CH 2 CO (ORc) , wherein Rc represents C 1 -C 4 -alkyl (branched or unbranched), adamantyl, optionally substituted phenyl, optionally substituted 1-naphthyl WO 01/27111 PCT/EPOO/09096 29 or 2-naphthyl or in each case optionally substituted
2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl or furoyl, CH 2 phenyl, CH 2 CH 2 Rd, wherein Rd represents optionally substituted phenyl, or CONHR*, wherein R* represents 5 Ci-C-alkyl (branched or unbranched), C 3 -C-cycloalkyl or optionally substituted phenyl, R 3 denotes methyl, ethyl, tert-butyl, C 3 -C-cycloalkyl, phenyl, optionally monosubstituted in the 3-, 5- or 6 10 position or optionally polysubstituted in the 4 position and additionally in the 2- and/or 3- and/or
5- and/or 6-position, phenoxy, optionally substituted naphthyl, optionally substituted pyrrole, optionally substituted pyridyl, optionally substituted furan, 15 optionally substituted thiophene, optionally substituted anthracene, optionally substituted phenanthrene or optionally substituted quinoline, with the proviso that R 3 does not denote n-propyl, 20 cyclohexyl, unsubstituted phenyl or phenyl monosubstituted in the 3-position with a carboxylic acid amide group if R' denotes tert-butyl, n-propyl, n butyl, 1,1,3,3-tetramethylbutyl, cyclohexyl, CH 2 CH 2 R (R = 4-morpholino), monosubstituted phenyl, 2,6 25 dimethylphenyl or benzyl and at the same time R 2 denotes hydrogen or -CO(methyl), and that R 2 does not denote hydrogen if at the same time R 1 denotes benzyl and R 3 denotes methyl, or at the same time R 1 denotes CH 2 C(O)tert-butyl and R 3 denotes unsubstituted phenyl, 30 in the form of the bases or of pharmaceutically acceptable salts. WO 01/27111 PCT/EPOO/09096 30 2. Bicyclic imidazo-3-yl-amines according to claim 1, characterized in that R 2 denotes hydrogen, R1 is selected from the group consisting of (CH 2 )nCN, 5 where n = 4, 5 or 6, cyclohexyl, CH 2 CO(Omethyl), 2,6 dimethylphenyl, 1,1,3,3-tetramethylbutyl, tert-butyl or n-butyl and R 3 is selected from the group consisting of 2-pyridyl, 10 3-pyridyl, 2-furanyl, 2-pyrroyl, methyl, tert-butyl, 3-hydroxyphenyl, 3,4-dimethoxyphenyl, 2,3 dichlorophenyl, 2,4-dichlorophenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 3-bromophenyl, 4-bromo-2 fluorophenyl, 5-bromo-2-fluorophenyl, 3-bromo-4 15 fluorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3 fluorophenyl, 3-methylphenyl, 3-phenoxyphenyl, 3-(4 chlorophenoxy)phenyl, 2-chloro-4-fluorophenyl, 2 chloro-6-fluorophenyl, 2,4-dimethylphenyl, 2,5 dimethylphenyl, 2-bromophenyl, 2-fluorophenyl or 2 20 (trifluoromethyl)-phenyl. 3. Bicyclic imidazo-3-yl-amines according to claim 1 or 2, characterized in that they are 25 (6-isocyano-hexyl)-(2-pyridin-2-yl-imidazo(1, 2 a]pyridin-3-yl)-amine, (2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-(6-isocyano hexyl)-amine, (2-cyclohexyl-imidazo[1,2-a]pyrazin-3-yl)-(6-isocyano 30 hexyl)-amine, (2,6-dimethyl-phenyl)-(2-furan-2-yl-imidazo[1,2 a]pyridin-3-yl)-amine, WO 01/27111 PCT/EPOO/09096 31 (2-furan-2-yl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid methyl ester, (2-cyclohexyl-imidazo[1,2-a]pyrimidin-3-ylamino) acetic acid methyl ester, 5 (2-methyl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid methyl ester, (2-pyridin-4-yl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3 tetramethyl-butyl)-amine, (2-methyl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3 10 tetramethyl-butyl)-amine, 3-(3-tert-butylamino-imidazo[1,2-a]pyridin-2-yl) phenol, butyl-[2-(2,3-dichloro-phenyl)-imidazo[1,2-a]pyrazin 3-yl]-amine, 15 [(2-phenyl-imidazo[1,2-a]pyridin-3-ylamino)-methyl) phosphonic acid diethyl ester, tert-butyl-(2-tert-butyl-imidazo[1,2-a]pyridin-3-yl) amine, butyl-(2-o-tolyl-imidazo[1,2-a]pyrimidin-3-yl)-amine, 20 (2,6-dimethyl-phenyl)-[2-(2-methoxy-phenyl) imidazo[1,2-a]pyrazin-3-yl]-amine, butyl-(2-o-tolyl-imidazo[1,2-a]pyrimidin-3-yl)-amine, tert-butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyrimidin-3 yl)-amine, 25 tert-butyl-(2-methyl-imidazo[1,2-a]pyridin-3-yl) amine, [2-(1H-pyrrol-2-yl)-imidazo[1,2-a]pyrimidin-3-yl] (1,1,3,3-tetramethyl-butyl)-amine, cyclohexyl-(2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl) 30 amine, tert-butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyridin-3 yl)-amine, WO 01/27111 PCT/EPOO/09096 32 tert-butyl-(2-pyridin-2-yl-imidazo[1,2-a]pyridin-3 yl)-amine, tert-butyl-(2-thiophen-2-yl-imidazo[1,2-a]pyridin-3 yl)-amine, 5 cyclohexyl-(2-methyl-imidazo[1,2-a]pyridin-3-yl) amine, N-cyclohexyl-N-[2-(5-methyl-furan-2-yl)-imidazo[1,2 a]pyridin-3-yl]-acetamide, tert-butyl-[2-(5-methylsulfanyl-thiophen-2-yl) 10 imidazo[1,2-a]pyrimidin-3-yl]-amine, [2-(3-bromo-thiophen-2-yl)-imidazo[1,2-a]pyridin-3 yl]-cyclohexyl-amine, acetic acid 2-methoxy-4-[3-(1,1,3,3-tetramethyl butylamino)-imidazo[1,2-a]pyrimidin-2-yl)-phenyl 15 ester, [2-(2-chloro-4-fluoro-phenyl)-imidazo[1,2-a]pyrimidin 3-yl]-(1,1,3,3-tetramethylbutyl)-amine, (2-anthracen-9-yl-imidazo[1,2-a]pyrazin-3-yl)-tert butyl-amine, 20 tert-butyl-(2-naphthalen-1-yl-imidazo[1,2-a]pyridin-3 yl)-amine, N-cyclohexyl-N-[2-(4,5-dimethyl-furan-2-yl) imidazo[1,2-a]pyrimidin-3-yll-acetamide or (1,1,3,3-tetramethylbutyl)-[2-(3,4,5-trimethoxy 25 phenyl)-imidazo[1,2-a]pyridin-3-yl]-amine. 4. Medicaments comprising as the active compound at least one bicyclic imidazo-3-yl-amine of the general formula I according to claim 1, in which R , R 2, R , X and Y 30 have the meaning given in claim 1, in the form of the base or of a pharmaceutically acceptable salt. WO 01/27111 PCT/EPOO/09096 33 5. Medicament according to claim 4, characterized in that it comprises as the active compound at least one bicyclic imidazo-3-yl-amine selected from the group consisting of 5 (6-isocyano-hexyl)-(2-pyridin-2-yl-imidazo[1,2 a]pyridin-3-yl)-amine, (2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-(6-isocyano hexyl)-amine, (2-cyclohexyl-imidazo[1,2-a]pyrazin-3-yl)-(6-isocyano 10 hexyl)-amine, (2,6-dimethyl-phenyl)-(2-furan-2-yl-imidazo[1,2 a]pyridin-3-yl)-amine, (2-furan-2-yl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid methyl ester, 15 (2-cyclohexyl-imidazo[1,2-a]pyrimidin-3-ylamino) acetic acid methyl ester, (2-methyl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid methyl ester, (2-pyridin-4-yl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3 20 tetramethyl-butyl)-amine, (2-methyl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3 tetramethyl-butyl)-amine, 3-(3-tert-butylamino-imidazo[1,2-a]pyridin-2-yl) phenol, 25 butyl-[2-(2,3-dichloro-phenyl)-imidazo[1,2-a]pyrazin 3-yl]-amine, [(2-phenyl-imidazo[1,2-a]pyridin-3-ylamino)-methyl] phosphonic acid diethyl ester, tert-butyl-(2-tert-butyl-imidazo[1,2-a]pyridin-3-yl) 30 amine, butyl-(2-o-tolyl-imidazo[1,2-a]pyrimidin-3-yl)-amine, (2,6-dimethyl-phenyl)-[2-(2-methoxy-phenyl) imidazo[1,2-a]pyrazin-3-yl]-amine, WO 01/27111 PCT/EPOO/09096 34 butyl-(2-o-tolyl-imidazo[1,2-alpyrimidin-3-yl)-amine, tert-butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyrimidin-3 yl)-amine, tert-butyl-(2-methyl-imidazo[1,2-a]pyridin-3-yl) 5 amine, [2-(1H-pyrrol-2-yl)-imidazo[1,2-a]pyrimidin-3-yl] (1,1,3,3-tetramethyl-butyl)-amine, cyclohexyl-(2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl) amine, 10 tert-butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyridin-3 yl)-amine, tert-butyl-(2-pyridin-2-yl-imidazo[1,2-a]pyridin-3 yl)-amine, tert-butyl-(2-thiophen-2-yl-imidazo[1,2-a]pyridin-3 15 yl)-amine, cyclohexyl-(2-methyl-imidazo[1,2-a]pyridin-3-yl) amine, N-cyclohexyl-N-[2-(5-methyl-furan-2-yl)-imidazo[1,2 a]pyridin-3-yll-acetamide, 20 tert-butyl-[2-(5-methylsulfanyl-thiophen-2-yl) imidazo[1,2-a]pyrimidin-3-yl]-amine, [2-(3-bromo-thiophen-2-yl)-imidazo[1,2-a]pyridin-3 yl]-cyclohexyl-amine, acetic acid 2-methoxy-4-[3-(1,1,3,3-tetramethyl 25 butylamino)-imidazo[1,2-a]pyrimidin-2-yl]-phenyl ester, [2-(2-chloro-4-fluoro-phenyl)-imidazo[1,2-a]pyrimidin 3-yl]-(1,1,3,3-tetramethylbutyl)-amine, (2-anthracen-9-yl-imidazo[1,2-a]pyrazin-3-yl)-tert 30 butyl-amine, tert-butyl-(2-naphthalen-1-yl-imidazo[1,2-a]pyridin-3 yl)-amine, WO 01/27111 PCT/EPOO/09096 35 N-cyclohexyl-N-[2-(4,5-dimethyl-furan-2-yl) imidazo[1,2-a]pyrimidin-3-yl]-acetamide or (1,1,3,3-tetramethylbutyl)-[2-(3,4,5-trimethoxy phenyl)-imidazo[1,2-a]pyridin-3-yl]-amine 5 or the pharmaceutically acceptable salts of these compounds.
6. Use of at least one bicyclic imidazo-3-yl-amine according to claim 1, 2 or 3 together with one or more 10 auxiliary substances for the preparation of a medicament for combating pain.
7. Process for the preparation of bicyclic imidazo-3-yl amines according to claim 1, 2 or 3 by a three 15 component reaction from amidine, aldehyde and isonitrile, characterized in that the synthesis of the compounds is carried out in methylene chloride as the solvent and in the presence of perchloric acid, the starting compounds being added in succession in the 20 sequence amidine, aldehyde and isonitrile and the products formed optionally then being reacted with a compound R Hal or an isocyanate ReNCO.
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| DE19948434A DE19948434A1 (en) | 1999-10-08 | 1999-10-08 | Substance library containing bicyclic imidazo-5-amines and / or bicyclic imidazo-3-amines |
| DE19948438 | 1999-10-08 | ||
| DE1999148438 DE19948438B4 (en) | 1999-10-08 | 1999-10-08 | Bicyclic imidazo-3-amine derivatives |
| DE19948434 | 1999-10-08 | ||
| PCT/EP2000/009096 WO2001027111A2 (en) | 1999-10-08 | 2000-09-18 | Bicyclic imidazo-3-yl-amine derivatives |
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| US20040077605A1 (en) * | 2001-06-20 | 2004-04-22 | Salvati Mark E. | Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function |
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